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DRUG EVALUATION
Drugs 1996 May; 51 (5): 820-845
0012 -6667/96/0005 0820/$26 00/0
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Losartan Potassium
A Review of its Pharmacology, Clinical Efficacy and
Tolerability in the Management of Hypertension
Karen L, Gon and Antona J. Wagstaff
Adis International Limited, Auckland, New Zealand
Various sections of the manuscript reviewed by:
J. Chan, Department of Clinical Pharmacology, The Chinese University of Hong Kong, Hong Kong;
NL. Gilchrist, Older Persons Health Division, The Princess Margaret Hospital, Christchurch, New Zealand;
E, Grossman, Hypertension Unit, Chaim Sheba Medical Center, Tel-Hashomer, Israel; A. Himmelmarn,
Department of Clinical Pharmacology, Sahlgrenska University Hospital, Goteborg, Sweden; S.E, Kjeldsen,
Department of Internal Medicine, Ullevaal University Hospital, Oslo, Norway; Y. Lacourcière, Hypertension
Research Unit, Centre Hospitalier de 1'Université Laval, Sante-Foy, Quebec, Canada; J. Lefebvre,
Hypertension Research Unit, Centre Hospitalier de 1'Universite Laval, Sante-Foy, Québec, Canada;
M. Nakashima, Department of Pharmacology, Hamamatsu University School of Medicine, Hamamatsu City
Japan; J.H. Pratt, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana,
USA; L. Ramsay, University Department of Medicine and Pharmacology Royal Hallamshire Hospital,
Sheffield, England; JM. Ritter, Department of Clinical Pharmacology, Guy's Hospital, London, England;
C.T. Stier Jr, Department of Pharmacology, New York Medical College, Valhalla, New York, USA;
K. Sugimoto, Department of Clinical Pharmacology, Jichi Medical School, Tochigi, Japan; K. Yoshinaga,
Tohuku Rosai Hospital, Sendai, Japan.
Contents
Summary
.............. ... .................................................................................................................... 821
1. Role of the Renin-Angiotensin System (RAS) in Hypertension ........................................................... 824
2. Pharmacodynamic Properties ...................................................................................................... 826
2.1 inhibition of Angiotensin II (All) Activity .................................................................................... 826
2.1.1 Inhibition of Receptor Binding . ..................................................................................... 826
2.1.2 Functional Antagonism of All Activity ......................................................................... 826
2.2 Effects on the RAS ................. . . . .......................................................................................... 827
2.3 Haemodynamic and Cardiovascular Effects .......................................................................... 827
2.3.1 EFfects on Left Ventricular Hypertrophy ...................................................................... 828
2.3.2 Other Effects ............ . ................................................................................................... 828
2.4 Effects on Renal Haemodynamics and Function ....................................................................829
2.5 Effects on Bradykinin . ....................................................................................................... ..…829
2.6 Metabolic and Neuroendocrine Effects ................................................................................. 829
3. Pharmacokinetic Properties .................................................................... ....................................... 830
3.1 Absorption and Distribution .................................................................................................... 830
3.2 Metabolism and Elimination .................................................................................................... 830
3.3 Drug Interactions ..................................................................................................................... . 831
4. Clinical Efficacy of Losartan Potassium in Hypertension .................................................................. . 831
4.1 Losartan Potassium Monotherapy ........................................................................................... . 833
4.1.1 Dose-Finding Studies ..................................................................................................... . 833
4.1.2 Comparisons with Other Antihypertensive Drugs ..................................................... ..… 833
4.2 Losartan Potassium plus Hydrochlorothiazide ......................................................................... . 834
4.2.1 Noncomparative Studies .............................................................................................. . 834
Losartan Potassium: Use in Hypertension
821
4.2.2 Dose-Finding and Comparative Trials ............................................................................ 834
4.3 Special Patient Groups ............................................................................................................ 836
4.4 Long Term Efficacy ................................................................................................................ . 836
5. Tolerabllity Profile ............................................................................................... . .................... ....... 836
5.1 Losartan Potassium Monotherapy. ....................................................................................... .. 836
5.1.1 Compared with Other Antihypertensive Drugs ................. . ......................................... 838
5.2 Losartan Potassium Plus Hydrochlorothiazide ......................... ……………………………………839
6. Dosage and Administration ............................................................................................................. 839
7. Place of Losartan Potassium in the Management of Hypertension ............. ................................... 840
Summary
Synopsis
Losartan potassium is an orally active, nonpeptide angiotensin II (AII) receptor
antagonist. It is the first of a new class of drugs to be introduced for clinical use in
hypertension. This novel agent binds competitively and selectively to the AII
subtype 1 (AT1) receptor, thereby blocking AII-induced physiological effects. An
active metabolite, E3174, contributes substantially to its antihypertensive effect,
which persists throughout 24 hours after once-daily administration.
In patients with mild to moderate hypertension, losartan potassium 50 to
100mg once daily as monotherapy lowers blood pressure to a similar degree to
enalapril, atenolol and felodipine extended release (ER). Losartan potassium
combined with hydrochlorothiazide reduces blood pressure further than either
drug given separately. About one-third of patients with severe hypertension have
responded to the combination product. Losartan potassium appears to be effective in elderly patients.
Losartan potassium is very well tolerated. In clinical trials, dizziness was the
only drug-related event reported more frequently with losartan potassium monotherapy than with placebo. First-dose hypotension is uncommon. An aspect of the
drug's tolerability profile which may prove to be particularly advantageous is
that it is associated with a similar incidence of cough to placebo in patients with
a history of ACE inhibitor-related cough. Additionally, clinically relevant adverse metabolic effects or laboratory abnormalities have not been documented
during losartan potassium therapy and renal function is preserved in patients
with or without renal insufficiency. The adverse effect profile of the losartan
potassium-hydrochlorothiazide combination resembles those for losartan potassium monotherapy and. placebo. Long term tolerability data are limited (<2
years) but support the very good tolerebility profile in shorter studies.
Elements of the drug's profile yet to be assessed or reported fully in the literature include long term efficacy, potential to favourably influence cardiovascular
and renovascular systems (and ultimately mortality) in patients with hypertension
and, lastly, cost effectiveness and influence on quality of life.
In summary, losartan potassium is the first AT1 receptor antagonist to become
available for the management of hypertension and, as such, it is an important
new antihypertensive agent. Pending long term data as outlined above, it is likely
to find initial use in patients with mild to severe hypertension who are unresponsive to, or intolerant of, their current therapy. However, with its novel mechanism
of action, good efficacy and favourable tolerability profile, losartan potassium
is well placed to claim a prominent position in the management of patients with
essential hypertension in the future.
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Drugs 1996 May; 51 (5)
Goa & Wagstaff
822
Pharmacodynamic
Properties
Pharmacokinetic
Properties
The action of angiotensin II (AII) at the AII subtype 1 receptor (AT1) is critical
to cardiovascular homeostasis: physiological consequences pertinent to hypertension include vasoconstriction, sodium/fluid retention, increased sympathetic
activity and cellular growth. Losartan potassium binds selectively, competitively
and with high affinity to the AT1 receptor, thereby blocking the activity of AII. It
has no clinically relevant affinity for any other pharmacological receptor at the
concentrations tested.
The active metabolite E3174 is a noncompelitive antagonist which binds to
the AT1 receptor with 10-fold greater affinity than its parent compound. E3174
is about 15 to 20 times more potent in inhibiting All-induced pressor and contactile responses, as shown in vitro and in vivo. Neither losartan potassium nor
E3174 possess any agonist activity at the AT1 receptor.
In patients with hypertension, losartan potassium increases plasma renin act i vi t y and plasma AII levels and appears to decrease plasma levels of aldosterone,
at least in the short term. Forearm vasodilator responses to bradykinin are not
altered by losartan potassium. Blood pressure decreases produced by once-daily
losartan potassium persist throughout 24 hours and heart rate is unchanged. Single
doses of losartan potassium and captopril (both 50mg) yielded similar quantitative effects on blood pressure, although the onset was slower in the first 3 hours
with losartan potassium. The influence of pretreatment plasma renin activity on
the antihypertensive effect of losartan potassium has not been determined, and
its influence on other haemodynamic or cardiac indices in patients with hypertension has not been well reported.
Preliminary data obtained in a few patients and evidence from numerous animal studies suggest that losartan potassium causes regression of left ventricular
hypertrophy (LVH); a large clinical study using losartan potassium is under way
to determine whether any clinical benefits are associated with LVH regression.
Losartan potassium improved mortality rates in animals prone to stroke and prevented librinoid necrosis of other end organs, including the heart, in various
animal models.
Renal function is preserved during losartan potassium administration in patients with hypertension with or without renal dysfunction. A uricosuric effect for
losartan potassium demonstrable in healthy individuals has been observed in
some but not all studies of patients with hypertension. Losartan potassium decreased proteinuria [including that associated with renal failure or with noninsulin-dependent diabetes mellitus (NIDDM)] in limited investigations. Plasma
levels of lipids/lipoproteins and prostaglandins are unchanged during losartan
potassium administration in patients without other concomitant diseases, as are
plasma norepinephrine levels and insulin sensitivity in patients without NIDDM.
The bioavailability of losartan potassium is about 33%, indicating a considerable
first-pass effect, and is not altered significantly by the presence of food. In most
patients about 14% of an oral dose of losartan potassium is metabolised via
hepatic carboxylation to the active metabolite E3174. However, in a very small
proportion of patients (< 1 %), enzymes responsible for metabolism to E3174 are
deficient (< 1 % of a dose is converted). Time, to achieve peak plasma concentration
is about 1 hour for losartan potassium and 3 to 4 hours for E3174. Blockade of
pressor response correlates more closely with plasma concentrations of the metabolite than with those of the parent drug. The volume of distribution is about
34L for losartan potassium and 12L for E3174: both compounds are >98% bound
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Drugs 1996 May; 51 (5)
Losartan Potassium: Use in Hypertension
823
to plasma proteins. The kinetics of losarlan potassium and E3174 are not influenced by multiple-dose administration.
At about 4 hours (in Japanese) and 6 hours (in Western individuals), the terminal elimination half-life of E3174 is longer than that of losartan potassium (2
hours). The pharmacokinetic properties of losartan potassium and E3174 are not
affected by renal dysfunction to any clinically important extent. In contrast, in
patients with hepatic dysfunction, plasma drug concentration of both agents is
increased and plasma clearance is reduced, necessitating dosage adjustment.
Pharmacokinetic studies using cimetidine and ketoconazole suggest that clinically significant interactions with losartan potassium and cytochrome P450
(CYP) 34A inhibitors are unlikely to eventuate. However, drugs that induce CYP
systems may hasten the metabolism of losartan potassium. No significant drug
interactions occur between losartan potassium and warfarin, digoxin or hydrochlorothiazide.
Clinical Efficacy
Tolerability
Losartan potassium is an effective treatment for hypertension. Large dose-finding
trials have shown losartan potassium 50mg daily as monotherapy to be superior
to placebo and indistinguishable from the l00mg dose. The drug has reduced
diastolic blood pressure (DBP) by about 8 to 13mm Hg in patients with mild to
moderate hypertension, as shown by several well-designed comparative trials
lasting 8 to 12 weeks. Antihypertensive efficacy as determined by trough blood
pressure values and percentage responders has not differed significantly between
losartan potassium and enalapril, atenolol or felodipine extended release (ER) in
comparative trials. Blood pressure lowering is evident within 1 week of initiating
losartan potassium therapy and is maximal by 6 weeks.
Approximately 30% of patients with severe hypertension have had their condition managed with losartan potassium plus hydrochlorothiazide 12.5 or 25mg
during 12-week noncomparative trials, with another 22% maintained on losartan
potassium monotherapy in 1 trial and the remainder requiring the addition of
atenolol and/or a calcium channel blocker. Overall decreases in DBP for regimens
containing losartan potassium were in the magnitude of 18mm Hg in this population. Compared with losartan potassium or hydrochlorothiazide monotherapy,
losartan potassium plus hydrochlcrothiazide reduced DBP by an additional 4 to
6mm Hg. Polydrug regimens incorporating losartan potassium were as effective
as similar strategies using enalapril.
Elderly patients have responded as well to losartan potassium as to felodipine
ER. Published evidence for the efficacy of losartan potassium in other special
patient groups is scant, as are long term efficacy data.
Results from double-blind trials involving a total of >2800 patients with hypertension who received losartan potassium indicate that the drug is very well tolerated. Although headache (14.1%), upper respiratory tract infections (6.5%),
dizziness (4.1%), asthenia/fatigue (3.8%) and cough (3.1%) have been reported
during administration of losartan potassium monotherapy, these are 'all events'
regardless of causality. Dizziness was found to be the only drug-related event
documented more often with losartan potassium than with placebo in the clinical
trials database. Orthostatic effects and first-dose hypotension are uncommon
(0.5% with 50mg). There have been rare reports of patients developing angioedema, migraine or ageusia during losartan potassium therapy.
Cough, which can limit treatment with ACE inhibitors, is seldom experienced
during losartan potassium therapy and its incidence is similar to that for placebo.
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Goa & Wagstaff
824
Dosage and
Administration
Spontaneous reports of cough occurred at a frequency of 3,1% for losartan potassium vs 2.6% for placebo. In trials conducted specifically in patients with a
history of ACE inhibitor-related cough, its incidence was similar for losartan
potassium (17 to 29%), placebo (35%) and hydrochlorothiazide (25 to 34%) but
was much less than with lisinopril (62 to 72%).
Comparisons without a placebo control showed that oedema was more common with felodipine ER (14%) and dizziness (7.4%) and insomnia (4.4%) were
more frequent with atenolol compared with losartan potassium. Liver enzyme
levels have risen to a minor extent in a few losartan potassium-treated patients,
but this rarely necessitates treatment withdrawal. The incidence of drug-related
adverse events and drug withdrawal using losartan potassium plus hydrochlorothiazide resembled that for losartan potassium alone and for placebo in clinical
trials.
The recommended initial and maintenance dosage of losartan potassium as monotherapy in patients with essential hypertension is 50mg once daily. Some patients
may benefit from 100 mg/day. Losartan potassium may be given with or without
food. In patients at high risk of hypotension or volume depletion and those with
hepatic dysfunction, the initial dose should be 25mg. No dosage adjustment is
needed for the elderly or patients with renal impairment. Losartan potassium is
not recommended for use in pregnant women because of the risk of fetal morbidity/mortality.
Japanese patients may receive losartan potassium 25mg daily.
The combination product containing losartan potassium and hydrochlorothiazide is started at a dosage of 50mg/12.5mg which can be doubled if the result is
unsatisfactory. This therapy is not recommended for use as initial treatment when
monotherapy would suffice, for patients with hepatic impairment or for those
with creatinine clearance 1.8 L/h (30 ml/min).
Losartan potassium (fig. 1) is an orally administered nonpeptide angiotensin II (AII) receptor antagonist. It is the first of a new class of antihypertensive drugs which act by directly blocking AII
subtype 1 (AT1) receptors. This novel action is the
basis for its application in patients with hypertension. An active metabolite, E3174, is largely responsible for the antihypertensive effect of the drug.
Losartan potassium is the prototype nonpeptide
AT1 receptor antagonist. As such, it has found considerable use as a pharmacological tool for investigation of the role of AII and its receptors in cardiovascular disorders. However, this review
concentrates on its clinical use in patients with hypertension when given as monotherapy or in combination with hydrochlorothiazide. Preclinical and
clinical evidence to date (reviewed by Smith et
al. [1] ) indicates that losartan potassium is also
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likely to be beneficial in patients with congestive
heart failure (CHF), but as yet too few data exist to
confirm its role in this indication.
1. Role of the Renin-Angiotensin System
(RAS) in Hypertension
The renin-angiotensin system (RAS) is central
to blood pressure regulation, fluid volume homeostasis and electrolyte balance. Figure 2 depicts the
major elements of the renin-angiotensin cascade:
the following discussion provides a simplified
overview of its physiological importance in cardiovascular disorders.
Briefly, renin is synthesised by the kidney and
secreted into the systemic circulation. Renin acts
on the substrate angiotensinogen to produce angiotensin I (AI), a decapeptide. AI is conyerted by
ACE and other enzymes such as chymases to the
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Losartan Potassium: Use in Hypertension
825
active hormone AII, which in turn is hydrolysed to
angiotensin III, another active substance, and to
other fragments including angiotensin IV. The
heart, vasculature and kidney are important sites
for the local production of AII
AII is the primary mediator of the RAS. It binds
to receptors located in virtually every tissue (see
section 2.1.1). The principal actions of AII critical
in maintaining normal blood pressure control are:
• direct and intense vasoconstriction of the
smooth muscle of the arterioles;
• release of aldosterone (and cortisol) from the
adrenal cortex;
• a direct antinatriuretic effect on the kidney to
increase proximal tubular reabsorption of so
dium, resulting in sodium and fluid retention.
Among other actions, AII may cause positive
inotropic effects and influences left ventricular
function. It also facilitates norepinephrine release,
Physiological
effects
Fig. 2. Site of action of losartan potassium. Simplified schematic
representation of the renin-angiotensin system and its interaction with bradykinin, highlighting site of action of losartan potassium and ACE inhibitors.
Fig. 1. Structural formulae of losartan potassium and its active
metabolite E3174.
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and thus sympathetic activity, and induces cellular
growth possibly implicated in left ventricular
hypertrophy (LVH).[2, 4]
The exact role of the RAS in hypertension is
complex and incompletely understood, although it
is established that small increases in plasma levels
of AII elevate blood pressure.[3] Inhibition of AII
has little effect on blood pressure in normotensive
sodium-replete individuals, whereas in sodium-depleted individuals the RAS is activated and blood
pressure drops markedly upon AII blockade. Compensatory rises in plasma renin occur in response
to decreased plasma AII levels.[4]
ACE inhibitors are unable to block the effects
of AII produced locally by systems other than the
RAS or to prevent formation of AII by enzymes
Drugs 1996 May; 51 (5)
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826
other than ACE, including endopeptidase and
chymases.[5] The rationale for developing specific
AII receptor inhibitors is, therefore, to antagonise
the activity of this crucial effector hormone independently of its source.
2, Pharmacodynamic Properties
2.1 Inhibition of Angiotensin II (All) Activity
2.1.1 Inhibition of Receptor Binding
Two distinct types of AII receptor, subtype 1
(AT1) and subtype 2 (AT2), were first identified in
rats[6,7] and are now known to exist in humans.[8,9]
Further receptor subtypes (AT1A and AT 1B) have
been discovered in rodent, but not in human, tissue.[10,11]
AT1 receptors are located primarily in vascular
and cardiac tissue but also in the brain, kidney and
adrenal gland, notably in the aldosterone-secreting
tissue of the zona glomerulosa. The function of the
AT2 receptor, which is present in brain, kidney and
adrenal medullary tissue, is poorly delineated. This
receptor is not thought to contribute to cardiovascular haemostasis,[2, 4,12] although a role has recently
been proposed in renal haemodynamics[13] and in
smooth muscle cell proliferation.[ 1 4 ] The part
played by AT1 receptors in mediating the complex
effects of AII (including those briefly outlined in
section 1), and thus in the pathogenesis of various
cardiovascular disorders, is comprehensively
reviewed elsewhere.[2,12,15]
Losartan potassium is highly and specifically
bound to AT1 receptors. It is 10 000 times more
selective for the AT1 than the AT2 receptor.[16] In rats,
losartan potassium l0mg/kg/day significantly (p <
0.05) reduced the density of AT receptors from
baseline in the liver, kidney and adrenal cortex,
sites of the AT1 receptor, but not in the adrenal medulla, where AT2 receptors predominate.[17] The
drug inhibits the specific binding of [125I]AII to the
AT 1 receptor site in a monophasic, concentrationdependent fashion, yielding an IC50 (concentration
inhibiting 50% of binding) of 1 to 2 x 10-8 mol/L in
isolated rat adrenal cortical microsomes and aortic
smooth muscle cells.[18,19] This contrasts with
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the IC50 of 10-4 mol/L estimated for losartan potassium at the AT2 receptor site.[16] E3174 has 10-fold
greater affinity than the parent drug for AT1 receptors, as shown by an ICso value of 1.1 x 10-9 mol/L
in rat aortic smooth muscle cells. [19]
In concentrations of up to 10-5 mol/L losartan
potassium has no affinity for any other receptor
types in rat tissue, e.g. -adrenoceptors in rat brain
and Ca++ receptors in rat cardiac ventricle, or for
other receptors (e.g. neurotensin, glycine, opioid,
muscarinic, dopaminergic, serotoninergic) in various isolated tissue preparations.[18,20,21]
2.1.2 Functional Antagonism of All Activity
Functional antagonism of AII activity, reflecting AT 1 blockade, has been demonstrated for
losartan potassium in vitro, in vivo and in healthy
volunteers.
In Vitro and In Vivo
Binding of losartan potassium to the AT1 receptor is saturable, reversible, and competitive.[22] In
concentrations of 10-8 to 10-7 mol/L losartan potassium caused parallel shifts to the right of the
concentration-contractile response or pressor response curve to AII The drug competitively
blocked AII-induced contraction of rabbit aorta
[percentage of maximal AII response (pA2) =
8.48],[18] guinea-pig ileum and rat uterus (pA2 = 8.5 for
both)[23] and All-induced pressor response in
conscious[24] or spinally pithed[25] rats. In none of
these test systems did the drug display any AII agonist effects in the concentrations tested (up to 10-5
mol/L),[18,23,25] and it had no effects on the enzymes
of the RAS.[18]
E3174 is also devoid of agonist activity, as
shown in similar experiments.[26] However, in contrast to losartan potassium, the metabolite is a noncompetitive antagonist, causing nonparallel shifts
to the right of the concentration-contractile response curve and displaying a pA2 value of 10.09
in isolated rabbit aorta.[26] E3174 is estimated to be
approximately 15 to 20 times more potent than
losartan potassium. This is based on ED30 values
(intravenous dose required to decrease mean arterial pressure by 30mm Hg) of 0.04 mg/kg for
E3174[26] vs 0.78 mg/kg for losartan potassium[27]
Drugs 1996 May; 51 (5)
Losartan Potassium: Use in Hypertension
827
Table I. Effects of losartan potassium on the renin-angiotensin system. Mean changes in plasma hormones of the renin-angiotensin
system in patients with hypertension 4 hours after the first dose and
after 6 weeks' daily administration of losartan potassium 100mg
(n = 13) or enalapril 20mg (n = 12)[36]
First dose
Mean plasma renin activitya
losartan
enalapril
Week 6
1 .54
1.89
1.73
2.75*
2.03*
0.28*
2.45
0.23*
Mean plasma angiotensin II levela
losartan
enalapril
Mean plasma aldosterone levelb
losartan
enalapril
.
-3.6*
-4.5*
-7.6*
-4.6*
a Ratio of change compared with baseline value.
b Mean change from baseline (ng/dl).
Symbol: * p < 0.05 vs placebo (placebo values not shown).
in renal hypertensive rats and on IC50 values for
inhibition of AII-induced cell growth and increase
in intracellular Ca++ levels in vitro.[19]
In Healthy Volunteers
In single oral doses of 20 and l00mg[28,29]
losartan potassium blocked the vasoconstrictor response to exogenous AI and AII in healthy individuals, as measured by forearm blood flow[28] and
change in dorsal hand vein diameter.[29] In contrast,
enalapril l0mg was effective only against AI.[28,29]
Similarly, the pressor response to exogenous AI
and AII was inhibited by up to 95% in a doserelated fashion by single and multiple oral doses of
losartan potassium 10 to 120mg.[30,31] With doses
40mg and higher this effect persisted for at least 24
hours.[31]
2.2 Effects on the RAS
Effects of losartan potassium on the RAS are
consistent with inhibition of AII activity (section
1). In healthy volunteers, losartan potassium
100mg in single[30,32,33] or multiple[30,34,35] doses
increased plasma renin activity[30,32-35] and plasma AII
levels[30,32,34] but produced inconsistent effects on
plasma aldosterone levels, compared with placebo.[30,32,34,35]
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These close-dependent effects are also apparent
during several weeks' therapy with losartan potassium in patients with essential hypertension (table
I),[36] with the exception that plasma aldosterone
levels appear to decrease, at least temporarily, during prolonged therapy. Plasma aldosterone levels
fell by 74% after 6 weeks' therapy with the 100
mg/day dosage[36] and by 17%[37] and 47%[38] after a
month with losartan potassium 50 mg/day. Increases in plasma renin activity and plasma AII
levels peaked at about 2 weeks and declined thereafter in 1 study,[36] whereas plasma renin activity
remained elevated at the end of 4 weeks' therapy
in patients with low baseline values.[38] Plasma renin
activity continued to rise over 12 months while
plasma aldosterone levels returned to normal in another trial in which some patients also received diuretics.[37] There was no significant change in the
proportion of active or inactive plasma renin
glycoforms following 6 weeks of losartan potassium therapy.[39]
Whether pretreatment plasma renin activity is
related to the antihypertensive effect of losartan
potassium is unknown. In hypertensive patients,
Goldberg et al.[36] found these changes in RAS parameters to be smaller than those previously observed in healthy volunteers, who have more responsive negative feedback systems which are
better able to inhibit renin release. Decreases in
mean arterial pressure have been correlated with
baseline levels of, and changes in, plasma renin
activity in a small study in patients with hypertension.[37] Animal models showed that losartan
potassium did not decrease blood pressure in low
renin models of hypertension such as deoxycorticosterone acetate salt-hypertensive rats[27] and the
bilateral nephrectomised rat.[40]
2.3 Haemodynamic and
Cardiovascular Effects
Losartan potassium reduces systolic and diastolic blood pressure (SBP; DBP) in patients with
essential hypertension (section 4). Placebo-adjusted
trough to peak ratios in patients with hypertension
were calculated as 60% for the 50mg dose, 72% for
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828
the l00mg dose[41] and 62 lo 85% for losartan potassium 50mg plus hydrochiorothiazide 6,25 or
12.5mg.[42] A ratio of 50% is considered indicative
of a duration of activity permitting once-daily
dosages, although the validity of this index has
been questioned.[43]
This aside, the effects of losartan potassium on
blood pressure have been shown to extend throughout a 24-hour period[44,45] (see also section 4). 24hour ambulatory blood pressure monitoring in 14
patients given iosartsn potassium 50 to 100mg for
12 weeks demonstrated mean DB'P decreases of
8mm Hg during the day (0700 to 1900) and 6.8mm
Hg at night (1900 to 0700).[45] Heart rate did not
change substantially in healthy individuals[34,35] or in
patients with hypertension (section 5).
The blood pressure-lowering effects of single
doses of losartan potassium 50mg and captopril
50mg were similar in sodium-depleted normotensive male volunteers and were additive when the
drugs were combined.[33] In hypertensive patients
receiving thiazides, the onset of action for a single
dose of losartan potassium 50mg was slower in the
first 3 hours than for captoprif 25mg. The magnitude of the effect on DBF was smaller with losartan
potassium but not significantly so.[46]
The influence of losartan potassium on other
haemodynamic parameters in patients with essential hypertension is not fully reported in the literature. Cardiac output, left ventricular ejection fraction and circulatory blood volume remained
unchanged and peripheral vascular resistance decreased in 10 Japanese patients treated with
losartan potassium 50 to l00mg for up to 10
weeks.[47] In spontaneously hypertensive rats with
pressure overload left ventricular dysfunction,
long term (12 weeks') administration of oral
losartan potassium 30 mg/kg/day decreased systemic arterial resistance, mean aortic pressure,
myocardial contractility and left ventricular end
diastolic pressure, and increased stroke volume and
volumetric aortic flow, compared with placebo.[48]
Losartan potassium enhanced the elasticity of a
medium-sized artery in 20 patients with essential
hypertension. Compliance of the radial artery, but
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not of the common carotid or femoral artery, increased by 50% after therapy with losartan potassium 50mg daily for 4 weeks (p = 0.02 vs placebo).[49]
2.3.1 Effects on Left Ventricular Hypertrophy
In patients with hypertension, development of
LVH amplifies the risk of end-organ damage and
associated morbidity (e.g. myocardial infarction,
stroke and heart or renal failure). Preliminary data
suggest losartan potassium administration is associated with regression of LVH, Losartan potassium 50
to l00mg administered daily to 15 patients for 12
weeks of a 16-week study reduced left ventricular
mass (LVM) from 196 to 191.5g and produced
small decreases (0.2mm) in interventricular septal
thickness and posterior wall thickness. In contrast,
atenolol in the same dosage increased LVM, although not significantly, and other parameters were
virtually unchanged.[50]
The vast majority of studies using animal models,[51-59] including those for low renin (renal aortic
coarction)[60] and high renin (2-kidney 1-clip renal
hypertensive rats) hypertension,[61-63] have demonstrated either a preventative or a regressive effect
of losartan potassium against cardiac hypertrophy
when the drug was administered in dosages of 0.5
to 40 mg/kg/day for 2 to 16 weeks.
2.3.2 Other Effects
Losartan potassium has improved survival and
prevented the development of cerebrovascular infarcts and cardiovascular and renovascular fibrinoid lesions in stroke-prone spontaneously hypertensive rats[64-66] and salt-loaded Dahl S rats.[67] The
drug was administered orally or by gavage in
dosages of 1 to 30 mg/kg/day for 8 to 20 weeks.
The effect was evident during losartan potassium
administration and persisted for 8 weeks after drug
discontinuation.[64] Losartan potassium (10 mg/kg/
day) reduced the collagen fibre content and thus
myocardial fibrosis in the 2-kidney, 1-clip hypertensive model.[63]
In other studies in rats, the drug inhibited the
incorporation of human low density lipoprotein
(LDL) into the hearts of normotensive animals[68]
Drugs 1996 May; 51 (5)
Losartan Potassium: Use in Hypertension
and decreased ADP-induced platelet aggregation
and thrombus weight.[69]
2.4 Effects on Renal Haemodynamics
and Function
Renal function is preserved during losartan potassium administration. Glomerular filtration rate,
renal blood flow, urine volume or other renal parameters were unchanged in healthy volunteers
following a single l00mg dose[32] and in patients
with hypertension given losartan potassium 50mg
daily for periods of 7 days to 1 year.[47,70-73] In patients
with renal insufficiency, creatinine clearance was
unaffected during losartan potassium therapy for
1[75] to 12 weeks.[138] Excretion of urinary electrolytes
(including sodium and potassium) in healthy
individuals on a low-salt diet was either
increased[32] or unaltered.[35] Hyperkalaemia has
been reported infrequently in clinical trials (section 5).
Uricosuria demonstrated in normal, [74] saltloaded[32] and salt-depleted[32] volunteers who received single[32,74] or multiple[74] doses of losartan
potassium 100mg was also observed in some[38,70] but
not other[37,71] trials in patients with hyperten- sion.
The mechanism of this effect is unknown. An
albumin-sparing effect (lowering of proteinuria) in
otherwise healthy patients with hypertension [72]
has also occurred in the presence of renal dysfunction[75,76] (including nondiabetic patients with
proteinuria >2 g/day)[76] and in elderly patients with
or without non-insulin-dependent diabetes
mellitus (NIDDM) [73] receiving losartan potassium.
2.5 Effects on Bradykinin
Degradation of the potent vasodilator bradykinin, and of substance P, is prevented by ACE inhibitors. The subsequent accumulation of bradykinin
may contribute to the mechanism of their antihypertensive action. Because losartan potassium
does not inhibit ACE (fig. 2), it would not be expected to produce elevated levels of bradykinin
which are also implicated in ACE inhibitor-induced
cough (section 5).
© Adis International Limited. All rights reserved.
829
This expectation is borne out by evidence to
date. Losartan potassium in single oral doses of 20
and 100mg did not affect forearm vasodilation induced by exogenous bradykinin infusion in healthy
volunteers, in contrast to enalapril l0mg. which potentiated this effect.[28] Eight-day administration of
losartan potassium 10 mg/kg every 12 hours intraperitoneally to. rats decreased blood levels of
bradykinin-(l-8) and renal levels of bradykinin(1-9) and bradykinin-(l-7),[77] suggesting that increased bradykinin levels are not contributory to
the drug's hypotensive action.
2.6 Metabolic and Neuroendocrine Effects
Serum levels of lipids or lipoproteins [total cholesterol, high density lipoprotein (HDL) cholesterol and triglycerides] have remained unchanged
during losartan potassium treatment for 4 weeks in
patients with mild hypertension but without
NIDDM.[78] In contrast, in a small sample of 8 patients, including 4 with NIDDM, serum cholesterol
levels dropped by 18% and LDL cholesterol levels
fell by 28%.[79] Serum total cholesterol levels were
also reduced by 8.8% among 11 patients with nephrotic syndrome who received losartan potassium
50 to 100mg daily for 1 month.[80]
The results of a small pilot study (n = 5) showed
improved insulin sensitivity and a 40% decrease in
plasma norepinephrine levels during treatment
with losartan potassium (50 mg/day for 6 weeks)
in patients with severe hypertension. [81] These
findings were not corroborated in larger placebocontrolled[36,78] or placebo run-in[37] trials which
found no significant change in insulin sensitivity
in patients with mild hypertension who were not
diabetic,[78] nor any reduction in plasma norepinephrine levels in patients with mild to moderate
hypertension.[36,37] The possible influence of disease
severity, prior therapy or duration of therapy on
these results is unknown.
In vitro, losartan potassium 100 nmol/L stimulated prostaglandin (PG) I2 release in human saphenous vein during exposure to AII.[82] However,
losartan potassium 50mg daily for 4 weeks did not
Drugs 1996 May; 51 (5)
830
Goa & Wagstaff
Table II. Pharmacokinetics of losartan potassium. Mean pharmacokinetic parameters of losartan potassium and its active metabolite E3174
after administration of a single 50mg dose of losartan potassium to healthy Western [86] or Japanese[87] volunteers
Parameter
Losartan potassium
E3174
Western[86]
Japanese[87]
Western[86]
Japanese[87]
0.19
0.25
0.46
0.29
Cmax (g/L)
1.3
4.1
3.0
tmax (h)
1.0
0.48
0.35
1.9
2.65
AUCo (g/L • h)
2.1
1.7
6.4
3.75
t1/2 (h)
4.2
3.2
6.1
6.9
Ae (% of dose)
CLR(L/h)
4.3
5.6
1.6
1.5
Abbreviations: Ae =fraction excreted in urine; AUG, = area under the plasma concentration-time curve from 0 to infinity; CLR = renal clearance; Cmaxmaximurn plasma concentration; tmax = time to Cmax; t1/2 = terminal elimination half-life.
alter renal or extrarenal PG synthesis in postmenopausal women with hypertension.[38]
Lastly, losartan potassium 50 mg/day for 9 days
did not affect adrenal function, as measured by
adrenal steroid biosynthesis, in patients with
hypertension.[83]
3. Pharmacokinetic Properties
Hepatic oxidation of losartan potassium yields
the pharmacologically active carboxylic acid metabolite E3174. [26, 84] The pharmacokinetics of both
Iosartan potassium and E3174 have been determined in healthy volunteers and in patients with
renal impairment, using high performance liquid
chromatography assay methods.[85] The major results
in healthy Western[86] and Japanese[87] volunteers are
summarised in table II.
The manufacturer's prescribing information is
cited in the text where other sources are lacking.
3.1 Absorption and Distribution
Oral bioavailability of Losartan potassium is approximately 33%[86] because of first-pass metabolism and is largely unaffected by food.[88] Peak
plasma concentrations (Cmax) of a single close of
losartan potassium are dose-proportional within
the range 25 to 200mg.[87] Time to achieve Cmax is
about 1 hour for Losartan potassium and 3 to 4 hours
for E3174 (table II). The area under the plasma
concentration-time curve (AUC) for 113174 is
about 4-fold[86] to 8-fold[87] greater than for losartan
potassium. Multiple-dose (up to 6 weeks) ad© Adis International Limited. All rights reserved.
ministration does not significantly alter the pharmacokinetics of losartan potassium or E3174.[36,87]
Losartan potassium was undetectable in plasma
at 10 hours post-dose whereas E3174 was measurable at 24 hours.[87] Plasma concentrations of
E3174 in healthy volunteers correlated more
closely with blockade of the pressor response than
did those of the parent compound.[3 1 ] Inhibition of
All-induced pressor effects was dose-dependent
within the range 40 to 120mg and reached a plateau
at E3174 concentrations of about 200 g/L.[3l]
Both compounds are >98% plasma protein
bound (98.7% for losartan potassium vs 99.8% for
E3174).[89] The volume of distribution is 34L for
losartan potassium[86] and 12L for the metabolite.[88]
In rats, losartan potassium crossed the blood-brain
barrier after a single intravenous dose (3 mg/kg)|[90]
but, of more clinical importance, not after single (10
mg/kg)[91] or multiple (3 mg/kg for 3 days)[92] oral
doses. Following a single oral dose, tissue losartan
potassium concentrations in the rat were highest in
liver and the intestine but were un-detectable in
muscle or fat.[9] The drug did not cross the placenta
in sheep,[93] but this model may not be applicable to
humans. Because of the risk of fetal abnormalities
losartan potassium is not recommended in
pregnancy (section 6).
3.2 Metabolism and Elimination
Tests in rats demonstrate a significant first-pass
effect for losartan potassium and indicate that E3174
is formed during uptake from the intestinal luDrugs 1996 May; 51 (5)
Losartan Potassium: Use in Hypertension
men.[91] About 14% of a dose (8% presystemic, 6%
systemic) is converted to this metabolite in most
individuals,[86] and several inactive metabolites are
also produced.[88] In a very small proportion of patients (< 1 %), enzymes necessary for metabolism to
E3174 are deficient (section 3.3).
The terminal elimination half-life (t1/2) is longer
for E3174 (about 4 hours in Japanese and 6 hours
in Western individuals) than for losartan potassium
(about 2 hours) [table II]. Renal clearance is 4.3[86]
to 5.6[87] L/h for losartan potassium 50mg and
about 1.5 L/h for its metabolite.[86,87] About 35% of a
radiolabelled oral dose is recovered in the urine
and 65% in the faeces.[88]
Less than 5% of a losartan potassium dose is
excreted unchanged renally in patients with normal
renal function.[94] Clinically relevant effects of renal impairment on the pharmacokinetics of losartan potassium would therefore be expected to be
minimal. This has been confirmed in patients with
varying degrees of renal insufficiency given
losartan potassium l00mg daily for 7 days. Renal
clearance of losartan potassium and E3174 decreased significantly in the group with the greatest
degree of renal dysfunction; however, AUC did not
change. Furthermore, decreases in the percentage
of losartan potassium excreted in the urine over 24
hours at steady state in patients with creatinine
clearance <1.8 L/h (30 ml/min) and increases in
t1/2(from 2.1 to 3.2 hours for losartan potassium
and from 10 to 13 hours for the metabolite) were
not considered to be important.[94]
On the other hand, in patients with mild, to moderate alcoholic cirrhosis plasma concentrations of
losartan potassium and E3174 increased 5-fold and
1.7-fold, respectively, oral bioavailability was
doubled and total plasma clearance was halved.[88]
Dosage adjustment is therefore required in this
population (section 6).
3.3 Drug Interactions
The major oxidative enzyme pathway responsible for the biotransformation of losartan potassium
is the cytochrome P450 (CYP) system, predominantly CYP2C9[95] although CYP3A(4) has also
© Adis International Limited. All rights reserved.
831
been shown to catalyse the reaction in vitro.[95, 96]
Studies in healthy volunteers showed that pretreatment with cimetidine increased AUC values for
losartan potassium (by about 20%) but did not affect the AUC for E3174 or Cmax for either compound.[97] Likewise, ketoconazole had no influence on the systemic conversion of losartan
potassium to E3 1 74 or on their plasma clearance.[98]
This suggests that significant drug interactions
with other CYP34A inhibitors are unlikely.
Conversely, the CYP inducer phenobarbital
(phenobarbitone) modestly but significantly reduced the AUC for both losartan potassium and
E3174.[99] The magnitude of change in this study
was too small to be clinically relevant, but it was
proposed that a more potent inducer might cause a
significant interaction. [99]
Conversion of losartan potassium to E3174 was
markedly deficient in <1% of participants in clinical trials. Two individuals with this rare defect who
converted <1 % of the parent drug to the metabolite
(compared with 14% in the general population,
section 3.2) were found to be homozygous for a
mutation in CYP2C9.[100] Other work indicates
that multiple phenotypic expressions exist for the
defect in cytochrome enzymes.[101]
In healthy volunteers, losartan potassium did
not alter the pharmacokinetics of single-dose warfarin[102] or intravenous or oral digoxin.[103] Hydrochlorothiazide had no effect on losartan potassium pharmacokinetics and vice versa [104]
4. Clinical Efficacy of Losartan
Potassium in Hypertension
Losartan potassium has been investigated both
as monotherapy and in combination with hydrochlorothiazide in randomised double-blind multicentre clinical trials, usually of 8 to 12 weeks' duration, involving a total of approximately 3700
patients. All comparative investigations included a
placebo washout or active control run-in period
and a placebo or active control during the main
body of the study. The drug was administered
orally and, almost invariably, once daily.
Drugs 1996 May; 51 (5)
Goa & Wagstaff
832
Table III. Efficacy of losartan potassium (L) in dose-finding studies and comparisons with other antihypertensive drugs in patients with mild
to moderate hypertension; all trials were randomised, double-blind and multicentre in design
a Defined as trough DBF <90mm Hg or DBP 90mm Hg but a decrease of 10mm Hg at study end.
b 24h ambulatory measurements.
c Abstract. Patients were hospitalised.
d
For per protocol analysis (blood pressure measured at trough).
Abbreviations and symbols: ATE = atenolol; bid = twice daily; C = captopril; DBP = diastolic blood pressure; E = enalapril; FELER = felodipine
extended release; SBP = systolic blood pressure; wk = weeks; y = years; = decrease; * p < 0.05, ** p < 0.01 vs placebo;†p < 0.05, †† p < 0,01
vs active comparator; > indicates superior efficacy for L or E based on statistical differences for UBP and percentage responders where
available, p  0.05; ≡ indicates equivalent efficacy.
Participants were diagnosed with mild, mode-ate or severe disease; the proportion of patients in
each category was not described in some trials.
With one exception,[105] all studies were conducted
© Adis International Limited. All rights reserved.
in outpatients. The primary efficacy measure was
mean absolute change from baseline in trough supine or sitting DBP and SBP. The percentage of
patients rated as 'responders' (trough DBP<90mm
Drugs 1996 May; 51 (5)
Losartan Potassium: Use in Hypertension
Hg or DBF 90mm Hg but reduced by  10mm Hg)
has been assessed in some instances.
4.1 Losartan Potassium Monotherapy
4. 1. 1 Dose-Finding Studies
Nelson et al.[105] first reported the efficacy of
losartan potassium in dosages 50mg daily in hospitalised patients. Subsequently, losartan potassium
in the 50 mg/day dosage has proved to be efficacious and superior to placebo in large placebo-controlled dose-finding trials in outpatients (table III).
Benefits of the 100mg daily dosage were similar to
those of 50 mg/day.[41,44] This latter regimen has been
adopted as the usual starting and maintenance
dosage in patients with mild to moderate hypertension (see section 6). Significantly more losartan
potassium recipients (41 to 54%) than placebo recipients (10%) were classified as responders at the
end of 4 weeks' therapy in 1 trial.[44]
Although some patients with severe hypertension have been maintained with losartan potassium
monotherapy after 12 weeks[110] most require addition of a diuretic with or without other antihypertensivc agents (section 4.2).
833
Percentage responders did not differ significantly between the losartan potassium group
(69%) or the felodipine group (76%)[109] or an atenolol group (50 vs 65%).[108] The latter 2 drugs
were similarly effective when patients were stratified according to disease severity (fig. 3).
There has been one comparison with captopril
which was given in a once-daily regimen.[107]
Losartan potassium produced a significantly
larger decrease in DBP but not SBP at weeks 6 and
12. At week 12, the percentage of responders for
losartan potassium (50%) was nearly twice that
for captopril (29%) [table III]. These results are,
however, unconvincing given that the dosage regimens used are not considered therapeutically
equivalent: indeed, 82% of captopril recipients (vs
60% with losartan potassium, p = 0.001) required
titration to a higher dose. A comparison is ongoing
of losartan potassium once daily versus captopril
administered in the more usual regimen of twice
daily.
Although losartan potassium appeared to be
less effective than enalapril according to an 'all
patients treated' analysis in a large trial of nearly
400 patients,[106] measurement of trough blood
4.1.2 Comparisons with Other
Antihypertensive Drugs
Losartan potassium reduces trough blood pressure in patients with mild to moderate hypertension
to a similar extent to the standard antihypertensive
agents with which it has been compared [enalapril,
atenolol, felodipine extended release (ER)] (table
III). Supine or sitting DBP fell by a mean of about
8 to 13mm Hg during 8 to 12 weeks' treatment with
Josartan potassium 50 to l00mg daily, compared with 10 to 14mm Hg for the other drugs (table III).
The largest mean decrease in DBP by losartan
potassium (13.2mm Hg) occurred in a study of 132
elderly patients: felodipine ER caused a reduction
of 14mm Hg.[109] A significant difference in DBP
favouring felodipine at week 6 disappeared at
week 12. Dosage titration was needed at week 6 in
62% of losartan potassium recipients and 51% of
patients given felodipine ER.
© Adis International Limited. All rights reserved.
Fig. 3. Clinical efficacy of losartan potassium vs atenolol. Mean
reduction from baseline in diastolic blood pressure at week 6
and week 12 in patients with mild or moderate hypertension
given losartan potassium 50mg (n = 132 in total) or atenolol
50mg (n = 66 in total) once daily for 12 weeks.[108]
Drugs 1996 May; 51 (5)
Goa & Wagstaff
834
Table IV. Noncomparative trials of losartan potassium (L) plus hydrochlorothiazide (HCT) in patients with severe hypertension (DBP 115rnm Hg)
Reference
Dunlay et al.[110]
Velivis et al.[111]a
Dosage (once daily) [mg]
L 50-100 ± HCT 1 2.5-25 ± ATE, CCB
L/HCTb 50-100/12.5-25 ± FEL5-10, ATE 50-100
No. of evaluable
patients
Mean decrease in trough sitting
SBP/DBP (mm Hg)
179
131
26*/19*
NR/18
a Abstract.
b Fixed combination tablet.
Abbreviations and symbol: ATE = atenolol; CCB = calcium channel blocker; DBP = diastolic blood pressure; FEL = felodipine; NR = not
reported; SBP = systolic blood pressure; * p < 0.001 vs baseline.
pressure values using a per protocol analysis
showed no differences in blood pressure reductions
or percentage responders between the 2 drugs (table III).
The antihypertensive effect of losartan potassium, like that of enalapril, is evident within 1 week
of starting treatment. In a large comparison in 526
patients,[41] clinically relevant reductions were
manifest within 1 to 2 weeks of starting therapy
with losartan potassium 50 to 150mg daily or enalapril 20mg daily and were maximal at 3 to 6
weeks after treatment initiation. Similarly, Dahlöf
et al.[l08] found that antihypertensive efficacy
reached a plateau at 6 weeks, with no further reduction discernable at 12 weeks.
4.2 Losartan Potassium plus
Hydrochlorothiazide
4.2.1 Noncomparative Studies
Table IV summarises noncomparative trials of
losartan potassium plus hydrochlorothiazide in patients with severe hypertension. This approach has
provided a satisfactory response in about one-third
of patients.
Among 179 participants in the Losartan Severe
Hypertension Study[11O] who began therapy with
losartan potassium 50mg, 22% continued with
losartan potassium monotherapy at week 12, 30%
received losartan potassium plus hydrochlorothiazide 12.5 to 25 mg/day and 46% received this last
regimen plus a dihydropyridine calcium channel
blocker or atenolol or both. The remaining. 2%
were prescribed regimens outside the protocol.
The overall decrease in blood pressure of
26/19mm Hg for all patients in this trial[110] resem© Adis International Limited. All rights reserved.
bled the reduction of 18.4mm Hg in DBP documented in a similar 12-week study[111] of 131 patients (31% Black). This latter result was obtained
using a regimen containing a tablet specifically formulated to contain losartan potassium 50mg/hydrochlorothiazide 12.5mg, with provision for the doubling of dose plus addition of felodipine and/or
atenolol. Approximately one-third of patients (data
from graph) were controlled with the combination
tablets only, but most also received felodipine.[111]
4.2.2 Dose-Finding and Comparative Trials
Weber et al.[44] found that the addition of
hydrochorothiazide 12.5mg daily for 2 weeks in
patients unresponsive to losartan potassium lowered DBP by a further 6.1 to 7.8mm Hg, similar to
the decrease of 6.4mm Hg in the placebo plus
hydrochlorothiazide group. Adding hydrochlorothiazide in doses 12.5mg to losartan potassium
50mg reduces DBP by an additional 4 to 6mm Hg
versus monotherapy with losartan potassium
50mg[112,113] or with hydrochlorothiazide 12.5mg[1l3] or
25mg[114] (table V).
For example, DBP was decreased by 13.2mm
Hg with losartan potassium 50mg plus hydrochlorothiazide 12.5mg versus 8,8mm Hg with losartan
potassium and 7.2mm Hg with hydrochlorothiazide.[113] Efficacy for the combination, as for
losartan potassium monotherapy (section 4.1.2),
was seen after 1 week and reached a maximum at
3 to 6 weeks.[114] The percentage of patients responding in this trial was greatest for losartan potassium plus hydrochlorothiazide 12.5mg (78%),
similar for losartan potassium plus hydrochlorothiazide 6.25mg (60%) and for losartan potassium
Drugs 1996 May; 51 (5)
Losartan Potassium: Use in Hypertension
alone (56%), and least for hydrochlorothiazide
(47%).[113]
As for monotherapy (section 4.1), regimens
containing losartan potassium produce equivalent
antihypertensive effects to those containing enalapril in direct comparisons (table V). Hydrochlorothiazide was added in 53% of 132 patients with
mild to moderate hypertension who initially received losartan potassium and in 47% of an enalapril l0mg group (n = 136).[1I5] Decreases in
DBP were significantly larger in the losartan po-
835
tassium group at 4 weeks, but not at study end, and
response rates did not differ (68% vs 60%).
Similarly, in patients with severe hypertension,
DBP fell by 27.7mm Hg with losartan potassium
plus one or more other drugs (hydrochlorothiazide
± calcium channel blockers ± atenolol) and by
30.9mm Hg with a comparable regimen containing
enalapril.[116] None of the reductions in DBP differed between groups at any of the measured intervals (weeks 1, 4 and 12).[116] At study end, 94% of 50
losartan potassium and 83% of 25 enalapril re-
Table V. Efficacy of losartan potassium (L) plus hydrochlorothiazide (HCT) in dose-finding and comparative studies with an active treatment
phase of 12 weeks in patients with mild to severe hypertension; all comparative studies were randomised, double-blind and multicentre in
design
a Abstract.
Abbreviations and symbols: ATE = atenolol; CCB = calcium channel blocker; DBP = diastolic blood pressure; E = enalapril; od = once daily;
SBP = systolic blood pressure; wk = weeks;  = decrease; ** p < 0.01 vs placebo or placebo-containing groups; > indicates significantly
greater efficacy for L groups, p < 0.05; ≡ indicates equivalent efficacy.
© Adis International Limited. All rights reserved.
Drugs 1996 May; 51 (5)
Goa & Wagstaff
836
cipients were receiving either drug plus hydrochlorothiazide and one other antihypertensive drug.
4.3 Special Patient Groups
Elderly patients have responded well to losartan
potassium. Blood pressure reductions were similar
for losartan potassium and felodipine ER in a study
conducted specifically in elderly patients (see section 4.1.2), and response did not differ between patients older or younger than 75 years,[109] Among 29
individuals (18% of total) aged 65 years in a
comparison with captopril,[107] age did not influence
the antihypertensive effect of either treatment.
Dahlof et al.[108] also found no differences in response to losartan potassium between younger and
elderly patients (>65 years) nor between male and
female patients (no quantitative data were presented). Patients 65 years or older showed a larger
mean reduction in DBP at 12 weeks with losartan
potassium (n = 25) than with enalapril (n = 30)
[12.7 vs 8.7mm Hg, p = 0.03], but the percentage
of responders was similar.[115]
This was also the case for the Black patients .
analysed in this study (losartan potassium = 32;
enalapril = 33). The DBP reduction was slightly but
significantly greater in the losartan group (10 vs
8mm Hg, p = 0.02)[115] The number of Black patients enrolled in other clinical trials (e.g. 12%[117]
and 19%[110]) has been too few to permit subgroup
analysis.
Blood pressure decreased significantly from
baseline (from 161/100 to 144/87mm Hg) in 89
patients with hypertension and various degrees of
renal failure who had received losartan potassium
50 to l00mg daily for 12 weeks.[138] Similar results
were earlier reported in 24 such patients treated for
7 days.[75] Compared with enalapril, losartan produced very similar effects on mean arterial pressure
in 11 patients with moderate renal dysfunction.[118]
Experience with losartan potassium is limited inother special groups such as those with NIDDM.
In a small trial in 8 patients (4 with NIDDM),
losartan potassium 50 mg/day with (6 patients) or
without (2 patients) atenolol 100 mg/day was effective over a 12-week period.[79]
© Adis International Limited, All rights reserved.
4.4 Long Term Efficacy
In a noncomparative trial, the antihypertensive
effects of losartan potassium persisted in the long
term. 70.7% (41 of 58) of a losartan potassium
monotherapy group (25 to l00mg daily) and 86.7%
(26 of 30) of those receiving concomitant thiazide
diuretics showed similar decreases in blood pressure at the end of a 52-week period to those recorded during the initial 8- to 10-week study.[l19]
Extended clinical experience will assist in establishing the long term profile of losartan potassium;
several such trials are underway (section 7).
5. Tolerability Profile
The following discussion is largely extracted
from a recent overview[120] of data obtained in clinical
trials of >3800 patients with mild, moderate or
severe hypertension. Of these, more than 2800 received losartan potassium with or without hydrochlorothiazide in double-blind comparisons with
placebo or with other antihypertensive drugs. The
major findings are illustrated in figure 4. No statistical analysis or methodological details of data collection were provided in the overview. Data from
separate comparative clinical trials are also included where contributory.
Dose,[41] age, gender or race[120] are reported to
have no influence on the tolerability profile of
losartan potassium; quantitative data for betweengroup comparisons are unavailable.
5.1 Losartan Potassium Monotherapy
As shown in double-blind trials, losartan potassium is very well tolerated. Among 2085 losartan
potassium and 535 placebo recipients usually
treated for 8 to 12 weeks, losartan potassium monotherapy produced a similar incidence of drugrelated overall events (15.3 vs 15.5%) and patient
withdrawal (2.3 vs 3.7%) to placebo. Drug-related
events experienced most frequently with losartan
potassium were headache (4.2%), asthenia/fatigue
(2%) and also dizziness, which was the only drugrelated event reported more frequently with losartan potassium than with placebo (2.4 vs. 1.3%).
Drugs 1996 May; 51 (5)
Losartan Potassium: Use in Hypertension
837
Fig. 4. Tolerability of losartan potassium. Percentage of patients with adverse events during therapy with losart an potassium (n =
2085), placebo (n = 535), ACE inhibitors (captopril, enalapril or lisinopril; n = 239) or losartan potassium plus hydrochloro thiazide
(HCT) [n = 858] in controlled trials of 8 to 12 weeks' duration. [120] Abbreviations: AE = adverse event; DRAE = drug-related adverse
event; URTI = upper respiratory tract infection.
When a causal relationship of events to treatment was not considered (fig. 4), the most commonly reported unwanted events in patients receiving losartan potassium monotherapy were headache
(14.1%), upper respiratory tract infection (6.5%),
dizziness (4.1%), and asthenia/fatigue (3.8%).
Cough was reported in 3.1 % of the losartan potassium group;[120] this adverse event is discussed
more thoroughly in section 5.1.1.
The incidence of oedema with both losartan potassium and ACE inhibitors was 1.7%, a rate similar to that for placebo (1.9%). Orthostatic effects
and first-dose hypotension appear uncommon, occurring in 0.5% of losartan potassium 25 to 50mg
and 2.2% of l00mg recipients.[120] One report has
described classic migraine in a patient without a
previous history of migraine.[121] Symptoms developed within 6 hours of the losartan potassium
50mg dose and were confirmed on rechallenge.[121]
Reversible ageusia also occurred in 1 patient receiving losartan potassium 25 mg/day: this symptom appeared within 3 weeks of commencing ther© Adis International Limited. All rights reserved,
apy and resolved within 2 to 3 weeks of treatment
discontinuation.[122]
To date there have also been 2 reports of angioedema during losartan potassium therapy. A patient
who was hypersensitive to penicillin and aspirin
developed facial rash and swelling considered by
the investigator to be angioedema.[88] Facial swelling
and flushing without dyspnoea occurred within 30
minutes of ingesting a 50mg dose of losartan
potassium in another patient with glomerulosclerosis and no history of angioedema, who had discontinued captopril because of cough. [123]
During long term losartan potassium treatment
(1 year) in 306 patients, headache (3.6%), dizziness (2.9%) and asthenia/fatigue (2.6%) were the
most common complaints.[120] Rebound hypertension has not been reported in clinical trials which
continued patient follow-up after abrupt losartan
potassium withdrawal.[107, 108, 120]
Levels of liver enzymes, usually alanine aminotransferase, have occasionally been elevated transiently during losartan potassium therapy (1.9%)[120]
Drugs 1996 May; 51 (5)
838
and these increases necessitated drug withdrawal
in one patient.[88] Hyperkalaemia (serum potassium
5.5 mmol/L) was documented in 1.5% of patients
receiving losartan potassium vs 1.3% of those
given ACE inhibitors but did not result in any
patient being discontinued.[120]
Apart from these alterations, no other changes
in laboratory indices were reported in the clinical
trials database.[120] There were no changes in
haematological or haemorrheological indices in 7
elderly patients treated with losartan potassium 50
to 100 mg/day for 52 weeks.[124] Losartan potassium
did not reduce heart rate in healthy individuals
(section 2.3) or in patients involved in the clinical
trials discussed in section 4 which measured this
parameter.
5.1.1 Compared with Other
Antihypertensive Drugs
Cough
Accumulation of bradykinin and substance P via
inhibition of ACE is thought to increase bronchial
reactivity and produce cough.[125,126] ACE inhibitorinduced cough can be sufficiently severe to limit
treatment.[126,127] Several 8-week double-blind trials
were designed specifically to assess the incidence
and severity of cough associated with losartan
potassium compared with hydrochlorothi-azide,
placebo or the ACE inhibitor lisinopril in patients
with a history of cough during ACE inhibitor
therapy.[128,129]
In the first study, involving 135 patients, cough
was documented in 71.7% of lisinopril patients
versus 29.2% of losartan potassium recipients (p <
0.01) and 34.1% of the hydrochlorothiazide group
(p< 0.01) [fig. 5].
The relative risk of developing cough in the
losartan group was 0.407 vs lisinopril and 0.854 vs
hydrochlorothiazide. A visual analogue scale
(VAS) confirmed that patients receiving lisinopril
perceived cough to be more frequent: VAS scores
increased by 3cm with lisinopril compared with
0.9cm for losartan potassium and 1.2cm for hydrochlorothiazide (p < 0.01 for both). Significantly
more women than men reported cough, as has been
observed by others.[126,127]
© Adis International Limited. All rights reserved.
Goa & Wagstaff
As well as being more frequent, cough was also
more severe with lisinopril, as evidenced by the
Symptom Assessment Questionnaire. Furthermore,
treatment duration was 18.6 days longer with losartan potassium and 13.2 days longer with hydrochlorothiazide than with lisinopril (p < 0.01). This
reflects the delay in onset to cough with these drugs
compared with the ACE inhibitor.[128]
Two additional studies, as yet not fully published, have shown similar results in patients with ACE
inhibitor-induced cough.[l29] In one, the percentage
of patients experiencing cough was 17% for the
lisinopril group, 25% for hydrochlorothiazide recipients and 69% for those given lisinopril. In the
other, the percentages of patients with cough in
losartan potassium, placebo and lisinopril groups
were 29%, 35% and 62%.[129] Losartan potassium
therefore was associated with an overall incidence
of cough (17 to 29%) similar to that of placebo
(35%) and hydrochlorothiazide (25 to 34%) and
Fig. 5. Losartan potassium and incidence of cough. Percentage
of patients with hypertension and a history of ACE inhibitorinduced cough who developed cough during daily therapy with
losartan potassium 50 mg (n = 48), hydrochlorothiazide 25mg
(n = 41) or lisinopril 20mg (n = 46).(128] * p < 0.01 vs other drugs.
Drugs 1996 May; 51 (5)
Losartan Potassium: Use in Hypertension
demonstrably less than with lisinopril (62 to 72%)
in patients with a history of ACE inhibitor-related
cough.
The high rate of cough in these studies is attributable to the selection of a cough-sensitive cohort.
Spontaneously reported cough is much less frequent: its incidence was 3.1% during treatment
with losartan potassium (n = 2085), 8.8% for ACE
inhibitors (enalapril, captopril or lisinopril; n =
239) and 2.6% for placebo (n = 535) in clinical
trials of up to 12 weeks' duration (no statistics
given).[201] Therefore, as in the above-mentioned
trials in patients predisposed to ACE inhibitor
cough, the incidence of cough in this overview of
clinical trials was similar for losartan potassium
and placebo.
Other Events
Asthenia/fatigue appears to be more frequent
with ACE inhibitors (6.7%) than with losartan potassium (3.8%) or placebo (3.9%) whereas the reverse is true for headache (14.1% for losartan potassium vs 10.9% for ACE inhibitors, but 17% for
placebo).[120]
Direct single-study comparisons with antihypertensive agents other than ACE inhibitors
demonstrated that, in the elderly, headache and oedema were more common with felodipine ER
(14% for each) than with losartan potassium (9 and
6.7%) but asthenia was more common with
losartan potassium (8 vs <1%).[109] It was not stated
whether the difference was statistically significant.
Similarly, although the overall incidence of adverse events for losartan potassium (49%) resembled that for atenolol (57%), more events in the
atenolol group (27%) than in the losartan potassium group (17%) were considered drug-related
and caused treatment discontinuation (6.9 vs 2.2%,
p < 0,05).[108] Headache was the most common
event for both drugs (16% with losartan potassium
and 19% with atenolol), but sweating and nausea
were significantly more frequent with atenolol (p
< 0.05).[108] It should be noted that these studies
lacked a placebo arm. Compared with losartan potassium therapy, dizziness (7.4 vs 4.1%) and insomnia (4.4 vs 1.1%) were more frequent with at© Adis International Limited. All rights reserved,
839
enolol and oedema/swelling (14 vs 1.7%) was
more common with felodipine in the overview of
double-blind trials.[120]
5.2 Losartan Potassium plus
Hydrochlorothiazide
With losartan potassium plus hydrochlorothiazide, the incidence of any drug-related adverse
event (14.8%) or event causing drug withdrawal
(2.8%) is similar to that for losartan potassium
alone and for placebo (fig. 4).[120] The tolerability
of the combination is difficult to assess when it is
used with other drugs. In noncomparative studies,
23% of 131 patients who received losartan potassium plus hydrochlorothiazide with or without atenolol and felodipine had a drug-related adverse
event.[111] Similarly, headache occurred in 26% of
180 patients with severe disease receiving polytherapy with losartan potassium plus hydrochlorothiazide with or without atenolol and a dihydropyridine calcium channel blocker.[110] One trial
comparing losartan potassium and enalapril, both
plus hydrochlorothrazide and other drugs, found
no differences in tolerability between the 2 approaches, [116] but no quantitative values were
given.
The rates of increased serum uric acid levels
(3.5%) and decreased serum potassium levels
(3.2%) with losartan potassium plus hydrochlorothiazide approximated those for the diuretic alone
(3.9 and 4.3%) when overviewed in all clinical
trials.[120]
6. Dosage and Administration
The recommended starting and maintenance
dosage of losartan potassium as, monotherapy in
patients with essential hypertension is 50mg once
daily. Some patients may benefit from receiving
l00mg once daily. A dosage of 25mg once daily
should be given to patients with hepatic impairment or volume depletion or who are otherwise at
high risk of hypotension. Hydrochlorothiazide
12.5mg daily may be added in patients not responding completely to losartan potassium.[88]
Drugs 1996 May; 51 (5)
840
In Japanese studies, the initial dosage of losartan potassium for mild to moderate hypertension
has been 25mg daily.
No initial dosage adjustment is necessary for
elderly patients or those with renal impairment, including patients undergoing dialysis. However, in
patients whose renal function may depend on an
intact RAS, losartan potassium may be expected to
be associated with worsening renal impairment.
Losartan potassium may be given with or without
food and with other antihypertensive agents.[88]
Losartan potassium is not recommended in
pregnant women because of the risk of fetal and
neonatal morbidity and death.[88]
The combination of losartan potassium and
hydrochlorothiazide is initiated at a dosage of
50mg/12.5mg daily (1 tablet). The dosage can be
doubled to 2 tablets daily (the recommended maximum). The product is not recommended for initial
therapy in patients with hypertension when monotherapy is the usual starting point, for patients with
hepatic impairment or for use in patients with creatinine clearance 1 .8 L/h (30 ml/min), who should
receive loop diuretics rather than hydrochlorothiaInformation regarding losartan potassium overdosage is limited. Supportive treatment should be
instituted if symptomatic hypotension occurs.
Losartan potassium and E3 174 are not removed by
dialysis.[88]
7. Place of Losartan Potassium in the
Management of Hypertension
Until recently, no new, classes of antihypertensive drugs had been introduced into clinical practice since the advent of ACE inhibitors in the late
1970s. Saralasin, the peptide prototype of a new
class, the AII receptor antagonists, was first synthesised and developed as a potential antihypertensive
agent earlier in that decade. This agent was investigated on the premise that blocking the AII receptor rather than inhibiting ACE would be expected
to impede the physiological actions of AII regardless of source and might also prevent associated
unwanted effects, such as bradykinin accumula© Adis International Limited. All rights reserved.
Goa &
Wagstaff
tion.[4] However, its partial agonist activity, short
duration of activity and lack of oral bioavailability
precluded its clinical use.[4, 131]
The shortcomings of saralasin have now been
circumvented with the development of nonpeptide
AT1 receptor antagonists. Losartan potassium is the
first orally active member of this class to become
available for clinical use in hypertension. It, is marketed alone and, in some countries, in fixed combination with hydrochlorothiazide,
Losartan potassium is highly and selectively
bound to the AT1 receptor, possesses no agonist
activity, and is metabolised to an active metabolite,
E3174, which contributes substantially to its antihypertensive effect. Its duration of activity persists
throughout a 24-hour period, as evidenced by 24hour ambulatory monitoring. Adverse metabolic
effects have not been documented and renal function is preserved during losartan potassium therapy. The drug has exerted a uricosuric effect in
some patients and in preliminary investigations has
decreased proteinuria. Losartan potassium is also
currently undergoing investigation in phase III trials for CHF,[1] including the Evaluation of Losartan
in the Elderly (ELITE) trial.[132]
Losartan potassium is an effective therapy for
hypertension. Data from well designed comparative studies of 8 to 12 weeks' duration in patients
with mild to moderate hypertension demonstrate
that the blood pressure-lowering effects of losartan
potassium 50 to l00mg once daily as monotherapy
are similar to those for the well-established agents
enalapril, atenolol and felodipine ER. A comparison with captopril once daily showed more favourable results for losartan potassium once daily; however, dosages used were not therapeutically
equivalent. A trial of losartan potassium once daily
vs captopril in the more common twice-daily regimen is currently underway.
The combination of losartan potassium plus hydrochlorothiazide produces larger reductions than
are seen with either drug alone and, in noncomparative 12-week clinical trials, about 30% of
patients with severe disease have been managed
with this combination. However, as is usual with
Drugs 1996 May; 51 (5)
Losartan Potassium: Use in Hypertension
patients in this category,[133,134] most require polytherapy (addition of a ( -blocker and/or calcium
channel blocker) to control blood pressure.
Losartan potassium appears beneficial in elderly patients, as evidenced by its similar efficacy
to felodipine ER in a large trial. Its role in the treatment of other special groups (Blacks or patients
with renal dysfunction or NIDDM) awaits definition by more thorough investigation and/or fuller
publication of preliminary study results.
Adverse effects commonly associated with
ACE inhibitors are cough, dizziness, first-dose hypotension, rash and fatigue. The tolerability of
losartan potassium has been assessed against this
established profile and those of other antihypertensive drugs. Data from >2800 patients given
losartan potassium with or without hydrochlorothiazide in controlled clinical trials of up to 12
weeks' duration demonstrate that the drug is very
well tolerated. Dizziness was the only drug-related
adverse event reported more frequently with
losartan potassium than with placebo. First-dose
hypotension has seldom been reported. There have
been rare instances of angioedema, severe migraine and reversible ageusia developing during
losartan potassium therapy.
ACE inhibitor-related cough is a class-specific
effect which can be sufficiently annoying to cause
treatment discontinuation in as many as half of patients developing this symptom.[127] The incidence
of cough varies according to the reporting method
used: it has been reported to occur in about 5 to
15% of all patients who receive ACE inhibitors[125,126] and has been documented in up to 20% of
patients in controlled trials.[126] Pulmonary accumulation of bradykinin subsequent to ACE inhibition is thought to be a main aetological factor in
cough development[126]
Clinical experience thus far has validated the
expectation that, because losartan potassium lacks
apparent effects on bradykinin, it would be associated with minimal cough. The incidence of cough
in trials specifically designed to assess this parameter in patients with a history of ACE inhibitorrelated cough was similar for losartan potassium
© Adis International Limited. All rights reserved.
841
(17 to 29%), hydrochlorothiazide (25 to 34%) and
placebo (35%) but, as expected, was greater for
lisinopril (62 to 72%). Spontaneously reported
cough among the general population was also documented at a similar frequency in losartan potassium and placebo groups. This property is likely to
be advantageous in patients at risk of developing
ACE inhibitor cough.
Guidelines for the pharmacological management of hypertension in the US[134] and the UK[133]
recommend initiation of therapy with diuretics or
-blockers - agents proven to reduce cardiovascular morbidity and mortality. ACE inhibitors, 1blockcrs and calcium channel blockers are positioned as 'alternative first-line' strategies in
patients in whom diuretics and -blockers are ineffective, contraindicated or poorly tolerated. However, other factors, such as concomitant disease,
potential for drug interaction, tolerability of the
agent and cost of treatment, should also be considered when initiating antihypertensive therapy[134]
and there is some controversy regarding the restrictiveness of these guidelines.[135,136]
Predictably, the ultimate position of losartan potassium among the plethora of drugs available for
the management of hypertension awaits clarification by long term efficacy data. At present, limited
long term tolerability data (<2 years) are available
but the results support the very good tolerability
demonstrated in 12-week trials. Several other important features of the profile of losartan potassium
requiring determination in future investigations
arc: (i) its effects, if any, on mortality in patients
with hypertension; (ii) the potential for cardiac and
renal benefits, vis-a-vis diabetic nephropathy, renal
glomerular hypertension, cardiac hypertrophy and
left ventricular function, as implied by animal
studies; (iii) whether long term unopposed AII
blockade, which exposes other angiotensin receptors to increased circulatory AII, will produce unwanted consequences; (iv) its effects on quality of
life and cost effectiveness.
This last issue is being addressed by the Trial
for Usual Care for Hypertension (TOUCH),[137] a 6month multicentre study designed to assess qualDrugs 1996 May; 51 (5)
Goa & Wagstaff
842
ity of life and cost parameters as well as the long
term efficacy of losartan potassium. Another recently-instigated trial, the Losartan Intervention
For Endpoint reduction in hypertension (LIFE)
study, seeks to evaluate whether any clinical benefits are associated with regression of LVH. The
trial, which compares losartan potassium with atenolol, is to be conducted in patients with hypertension and LVH. It aims to enrol 8300 patients and
will continue for at least 4 years or until 1040 pa-tients
have experienced myocardial infarction, stroke or
cardiovascular death.[129]
In summary, losartan potassium is the first of a
new class of drugs, the AT1 receptor antagonists, to
be introduced for the treatment of hypertension. As
such it is an important new agent. Pending long
term efficacy and mortality data the drug is likely
to find initial use in patients who are not well managed with, or are intolerant of, their current therapy.
However, with its novel mechanism of action, good
efficacy and favourable tolerability profile, losartan potassium is poised to claim a prominent position in the management of patients with mild to
severe essential hypertension.
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E-mail: [email protected]
Errata
Vol. 46, No. 3, page 387: In table II, the half-life of pergolide should read 75-42 (mean 27) hours.
[Montastruc JL, Rascol O, Senard JM. Current status of dopamine agonists in Parkinson's disease. Drugs 1993 Sep; 46 (3): 384-93]
Vol. 51, No. 5, page 838: In the fifth paragraph of section 5 .1.1, the second sentence should read, '. . . 17% for the losartan potassium
group…..’
page 845: In reference no. 106, the journal name should read J Hypertens.
[Goa KL, Wagstaff AJ, Losartan potassium: a review of its pharmacology, clinical efficacy and tolerability in the management of
hypertension. Drugs 1996 May; 51 (5): 820-45]
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Drugs l996 Oct;52(4)